Almost all organisms have an innate sense of time. From cyanobacteria to humans, intrinsic circadian clocks profoundly influence physiology and behavior on a 24-hour basis. For example, we sleep and wake every day at about the same time. Our knowledge of the molecular mechanisms underlying circadian rhythms in many organisms including humans has benefited immensely from the genetics of Drosophila melanogaster. Although we have a good understanding of how circadian oscillations are generated, we know little about the signal transduction mechanisms that synchronize the circadian clock with daily changes in light intensity. This is a fundamental question, because circadian rhythms need to be properly synchronized to be beneficial. In Drosophila melanogaster, a dedicated circadian light input pathway has been identified: CRY (CRYPTOCHROME) is the photoreceptor and TIM (TIMELESS) the target molecule within the pacemaker. We will use the powerful molecular, cellular and genetic tools that Drosophila offers to achieve our goal: understanding at a molecular level how light activates the CRY input pathway to synchronize the circadian pacemaker. Three major lines of investigation will be followed. The first aim will test the hypothesis that light triggers a change in CRY conformation that alters its stability and its ability to bind to target proteins. With the second aim, we will characterize genes identified as promising candidates for their involvement in the CRY light input pathway. Finally, with the third aim, we will identify novel components of this pathway by performing an unbiased screen for mutants that alter circadian photo responses. Combined, these approaches should fundamentally advance our understanding of circadian photoreception. Our work will also contribute to understanding general principles of circadian rhythm generation and the process of circadian entrainment. Recent appreciation of the clinical relevance of human circadian rhythms and the morbidity caused by their dysfunction, as occurs in shift workers, makes understanding of these basic mechanisms an important objective [unreadable] [unreadable]